Promise in the Pipeline

New treatment options for Stage IV melanoma offer hope to people with metastatic skin cancer.

Britta Fortson was 18 years old when she was diagnosed with ocular melanoma (cancer of the eye), but she responded well to treatment and went to college a few months later as planned. During the following two decades, she started running marathons, became a speech pathologist, got married, and had two children. Then, in the spring of 2015, her primary care doctor noticed elevated liver enzymes on one of her routine blood tests. Further testing revealed that the melanoma had returned and had metastasized to her liver.

I was devastated, says Britta, now 43, of Jacksonville, Florida. When I started reading studies online, it looked like most people with Stage IV melanoma lived for about six months. I couldnt function and started planning for my demise.

Brittas sister began researching treatment options, and she urged Britta to see a doctor at MD Anderson Cancer Center in Houston who specialized in immunotherapymedications that stimulate the immune system to recognize and destroy cancer cells.

In the past few years, weve seen a real revolution in our therapies for late-stage melanoma, says Sapna Patel, MD, Brittas physician in the Department of Medical Melanoma Oncology at MD Anderson. Weve been aware of drugs that can activate the immune system, but in the past they were used for rare cases and had serious side effects. The new treatments are benefiting a larger population and have more reasonable side effects.

Britta was accepted into a clinical trial and started taking a combination of two immunotherapy drugs in August 2015. About 60 percent of patients typically respond to this treatment, says Dr. Patel, and Britta anxiously waited to see if she would be in that group.1 She flew to Houston every three weeks for infusions of the medications, and after three months CT (computed tomography) scans revealed good news: two of the tumors were almost gone and two were smaller. Britta continues to take the medication and appears to have no cancer in her body.

Outsmarting Cancer Cells

In the United States, the rates of melanoma have been increasing for the past 30 years, according to the American Cancer Society.

Its becoming more and more frequent, and one reason for this may be the fact that people are out in the sun wearing less clothing than in the past, says Elizabeth Buchbinder, MD, a medical oncologist at the Melanoma Treatment Center at the Dana-Farber Cancer Institute in Boston.

About 76,000 new melanomas were diagnosed in 2016, and more than 10,000 people died from the disease.2 Roughly 15 to 30 percent of people with melanoma are diagnosed with Stage IV diseasecancer that has spread to other parts of the bodyand these people typically live less than a year after diagnosis, Dr. Patel says.

Shailender Bhatia, MD, an associate professor of medicine in the Division of Medical Oncology at the University of Washington School of Medicine in Seattle, has been studying innovative melanoma treatments for more than a decade. For years researchers were trying new things that kept failing, Dr. Bhatia says. But weve made tremendous progress recently, and in the past five years more than 10 new treatments have been approved by the FDA [US Food and Drug Administration].

One promising new therapy is a group of drugs known as immune checkpoint inhibitors. Cancer cells proliferate by hiding from the bodys immune system, and these medications help the immune system recognize cancer cells as invaders. In many cases, patients start on what is known as a PD-1 inhibitor, says Dr. Bhatia: Cancer cells have different methods of hiding from the immune system, and one strategy is pushing a brake on immune cells so they slow down. PD-1 inhibitors essentially prevent the cancer cells from seeing the brake on the immune cells, which allows the immune system to stay active and do its function.

If the cancer does not adequately respond to a PD-1 inhibitor, Bhatia may suggest that the patient consider adding a drug known as a CTLA-4 inhibitor, which uses a similar mechanism to help the immune system.

Although a combination of immunotherapy drugs increases the chances of success, the side effects are usually more significant, says Dr. Buchbinder: For some patients the immune system gets overstimulated and attacks tissues in areas like the bowels, liver, lungs, and skin, but we can prescribe medications to manage the symptoms.

Managing Side Effects

Because ocular melanoma can be particularly aggressive, Britta started immediately on a combination of two checkpoint inhibitors known as Opdivo® (nivolumab) and Yervoy® (ipilimumab). Within a few weeks, she was experiencing diarrhea, lung inflammation, fatigue, and arthritis in her knees, hands, and feet. Her doctor prescribed an inhaler to treat the chest pain and coughing and an anti-inflammatory drug for the arthritis.

Even though I had to stop working due to the side effects, I feel like my symptoms are under control, says Britta. I try to go running early in the morning because the joint pain increases throughout the day, and I usually have to take a nap due to the fatigue.

Britta does not know whether she will continue taking the immunotherapy drugs after the clinical trial, but some patients with Stage IV melanoma stay in remission even after discontinuing medication. This occurs when the immune system starts replicating the drugs mechanism independently.

This is really the goal of immunotherapy, Dr. Patel explains. When we get a flu shot, we are immunized for the year, and in melanoma there should be a handoff from the drugs to your own immune system. We are not sure when that handoff occurs and why it happens in some people and not others.

Former president Jimmy Carter, whose melanoma spread to his brain and lungs, was prescribed a checkpoint inhibitor known as Keytruda® (pembrolizumab) for six months in 2015, and he has remained cancer-free even after discontinuing the medication.

Targeted Therapy

While immunotherapy empowers the immune system, researchers have also recently pioneered new chemotherapy treatments that target melanoma cells directly. Traditional chemotherapy drugs kill all cells that grow rapidly, which can lead to nausea, hair loss, sores in the mouth, low white blood cells counts, and other symptoms.

The newest chemotherapy drugs specifically target melanoma tumors that have what is known as a BRAF gene, which occurs in about 50 percent of cases.3 This mutation leads to a hyperactive protein that causes melanoma cells to multiply rapidly, and the new treatments bind to this mutation and prevent it from growing. Something known as MEK proteins work together with the BRAF proteins, and the FDA has also approved new drugs that target the MEK proteins.

These targeted therapies have far fewer side effects than traditional chemotherapy, but they are typically effective for only about a year because the cancer cells usually find a way to avoid the drug mechanism, says Dr. Buchbinder. We usually use these drugs for extending life rather than eliminating cancer, she explains. If a patient is in a lot of discomfort and needs a quick response, these medications can be used in combination.

The Next Frontier

While the latest treatments are offering hope to people who previously had few options, dermatologists like Whitney High, MD, advises consumers to avoid the temptation to view these drugs as a substitute for protecting themselves against the dangers of too much sun exposure.

In the end, the best thing we can do is avoid getting melanoma in the first place, says Dr. High, director of dermatology at the University of Colorado School of Medicine in Aurora. He urges people to apply sunscreen generously, especially between the hours of 10 a.m. and 2 p.m.the hours with the most direct sunlight. Melanoma is on the rise, and people do not seem to be aware of how much damage the sun does to skin.

The innovative treatments approved in the past several years are saving lives, but for now only a little more than half of patients are responding to these medications. Britta knew a woman with Stage IV melanoma who was in the same clinical trial, but the woman died in August.

Dr. Bhatia predicts that the next wave of research will explore whether using immunotherapy drugs in combination with targeted gene therapy will increase the survival rates for patients with late-stage melanoma. Studies are also under way to determine the effectiveness of using immunotherapy treatment on patients with Stage III melanomacancer that has spread to the lymph nodes. More people with melanoma are surviving than ever before, and the goal, he says, is to continue that trend into the future.

The most remarkable thing is watching these patients live longer while enjoying an excellent quality of life, says Dr. Bhatia. While we do not know definitively if they are cured, many are in complete remission and just come in for surveillance scans. We have the happy problem of dealing with an increased volume of survivors in our clinic mostly receiving maintenance treatment.

1 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine. 2015;373(13):23-34. doi: 10.1056/NEJMoa1504030.

2 Key statistics for melanoma skin cancer. American Cancer Society website. Available at: . Accessed January 9, 2017.

3 Targeted therapy for melanoma skin cancer. American Cancer Society website. Available at: . Accessed January 9, 2017.

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